1. Field of the Invention
This invention relates to improved processes to produce 2',3'-dideoxy-2',3'-didehydronucleosides.
2. Description of the Background and Related References
Acquired immunodeficiency syndrome (AIDS) is the result of an infection by human immunodeficiency virus(es) (HIV)..sup.1 This retrovirus shows a specific tropism for the helper/inducer T cells.sup.2 leading to their depletion. The resultant immunosuppression predisposes HIV patients to life-threatening opportunistic infections.
Although at present there is no cure for AIDS, one nucleoside derivative, 3'-azido-3'-deoxythymidine (AZT, Retrovir.TM.), has already proved to be an efficacious agent in the treatment of AIDS in clinical trials and has been licensed by the appropriate regulatory agency for use in patients with AIDS..sup.3 A number of other chemical and biological agents have been reported to have biological activity against HIV. 2',3'-Dideoxycytidine (ddC), 2',3'-dideoxyadenosine (ddA),.sup.4 2',3'-dideoxy-2',3'-didehydrocytidine (d4C),.sup.5 suramine and its analogs,.sup.6 ribavarin,.sup.7 foscarnet,.sup.8 HPA-23,.sup.9 d-penicillamine,.sup.10 castanospermine,.sup.11 fusidic acid,.sup.12 3'-azidoguanosine (AZG),.sup.13 and 3'-fluoro-3'-deoxythymidine (FDDT).sup.14 are all reported to be active against HIV.
A number of reports have appeared in the literature which have shown that 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) possesses in vitro activity against HIV in several cell lines..sup.15
2',3'-dideoxy-2',3'-didehydrothymidine (d4T) has been prepared by Horwitz et al. by two different routes. .sup.16, 17 The first of these synthetic routes involves subjecting the 3',5'-anhydro derivative of thymidine to elimination reaction conditions. The second of these routes involves subjecting the 5'--O-protected 2,3'-anhydro nucleoside derivative of thymidine to ring-opening elimination reaction conditions.
The use of anhydro nucleosides as intermediates for nucleoside synthesis is well precedented in the literature in the art to which the present invention pertains..sup.18
With the recent discovery of the potency of 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) as an anti-HIV agent, a process which allows 2',3'-dideoxy-2',3'-didehydronucleosides, including d4T, to be prepared cheaply on a large scale becomes important.
The Horwitz route to produce d4T from the 3',5'-anhydro compound.sup.16 is not feasible on a large scale because complete removal of the large volume of DMSO used in scale-up of the Horwitz procedure is very difficult to achieve and requires high vacuum (0.01 mmHg and heating for the temperature range of about 40.degree.-50.degree. C.) for an extended period of time. These conditions lead to cleavage of the glycosidic bond to give thymine as an undesired side product. Also, prolonged exposure to basic conditions, which are required when solvents other than DMSO (e.g. THF, DMF) are used leads to decomposition of d4T to, again, give thymine as an undesired side product.
The alternative Horwitz procedure requires protection of the 5'--OH position before formation of the 2,5'-anhydronucleoside. This 2,5'-anhydronuclesodie can be opened to give the 5'--O-protected nucleoside.
The desired 2,3'-anhydro nucleoside can be prepared directly by reacting thymidine with diethyl-(2-chloro-1,1-2-trifluoroethyl)amine..sup.19